A Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Preliminary Analysis of RTOG 9413

Heather Jones, MD
University of Pennsylvania Cancer Center
Last Modified: November 6, 2001

Presenter: M. Roach III
Presenter's Affiliation: Radiation Oncology, UCSF, San Francisco, CA
Type of Session: Plenary

Background
Many unanswered questions await definitive resolution in the treatment of prostate cancer. There has been significant controversy in the field of radiation oncology regarding the optimal field size and ideal integration of hormonal therapies. This particular trial tests the hypothesis that: 1.TAS and WP radiotherapy (RT) followed by a prostate boost improves the progression-free survival (PFS) by at least 10% compared to TAS and PO RT. 2. This trial also test the hypothesis that neoadjuvant (NHT) followed by concurrent TAS and RT improves the PFS compared to RT followed by adjuvant TAS (AHT) by at least 10%. Secondary objectives included comparing treatments with regard to local control, time to distant failure and overall survival (OS). This trial is an initial report of RTOG 9413.

Materials and Methods

1323 men with clinically localized adenocarcinoma of the prostate with an elevated prostate specific antigen (PSA) < 100 ng/ml were included in this study.

Patients were stratified by T stage, PSA and Gleason Score (GS) and required to have an estimated risk of lymph node (LN) involvement >15%.

TAS consisted of flutamide 250 mg 3 x day and either leuprolide or goserelin acetate depot administered two months before and during RT (NHT) or for 4 months following the completion of RT (AHT).

Arm 1- 325 men were randomized to WP RT+NHT

Arm2 - 324 men were randomized to PO RT+NHT

Arm 3- 323 men were randomized to WP RT+AHT and

Arm 4 - 323 men were randomized to PO RT+AHT

The median age for all patients was 70 years and nearly 25% were of African-American origin.

The median PSA was 22.8 ng/ml, 67% of patients had T2c-T4 disease and 72% had a GS of 7-10.

PSA failure was defined as two consecutive rises or a PSA > 4ng/ml at the last follow-up after the value PSA nadir was reached.

Results

The median follow-up since study entry for all patients was 59.3 months.

Patients treated with WP RT experienced a 4-year PFS of 56% compared to 46% when treated with PO RT (p=0.014). No difference is yet seen in OS between these groups.

Patients treated with NHT experienced a 4 year progression free survival of 53% vs 48% for AHT (p=0.33) and no survival advantage as of yet.

Comparing all four arms, there was a PFS advantage for WP RT +NHT compared to PO RT+NHT, WP RT+AHT or PO RT+AHT (61% vs. 45, 49 and 47% respectively, p=0.005).

However, no OS advantage is yet seen.

Grade 3 or higher GU and GI toxicities where not clinically significantly different between patients treated on any of the four arms.

Author's Conclusions
This preliminary analysis demonstrates that Whole Pelvis RT is associated with an improvement in PFS compared to Prostate Only RT in patients with a risk of lymph node involvement >15%. The failure to see an early advantage in PFS with NHT compared to AHT may result from the fact that the time from the date of randomization to discontinuation of TAS is two months later on the AHT arms. Further analysis suggests that WP RT+NHT may be best in terms of PFS (p=0.011) and OS (p=0.12). Longer follow-up is required to confirm the trends seen in this preliminary report since the median survival is not likely to be reached for several years.

Clinical/Scientific Implications
This study attempts to tackle two issues in the treatment of prostate cancer 1. the treatment volume and 2. the use of hormones neoadjuvantly versus adjuvantly. Early results would seem to indicate that neoadjuvant HT and whole pelvis irradiation as an advantage over adjuvant HT and prostate alone RT. However, the followup in this study is too short to make sweeping recommendations. When the data does mature, we can hope to gain some insight into the whole pelvis vs prostate only volume issue. A major question remains: Is it treatment of the lymph nodes that improves the outcome or just the treatment of the periprostatic tissues with the larger pelvic fields. Also, the definition of PSA failure used in this study is not the currently endorsed recommendation and may influence the reported PSA failure rate in this study. In RTOG 9413, we have yet another study that demonstrates that the addition of neoadjuvant androgen ablation to definitive radiation therapy is associated with a highly significant improvement in local control and freedom from disease progression; its impact on survival remains an open question.

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